在人源化小鼠移植后单独使用环磷酰胺或与托珠单抗联合使用后,移植物抗白血病免疫力得以保留

IF 4.6 2区 医学 Q2 IMMUNOLOGY Clinical & Translational Immunology Pub Date : 2024-03-15 DOI:10.1002/cti2.1497
Chloe Sligar, Ellie Reilly, Peter Cuthbertson, Kara L Vine, Katrina M Bird, Amal Elhage, Stephen I Alexander, Ronald Sluyter, Debbie Watson
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引用次数: 0

摘要

目的 供体造血干细胞移植通过诱导移植物抗白血病(GVL)免疫来治疗白血病。然而,移植物抗宿主疾病(GVHD)往往会减轻这种益处,在人源化小鼠中,移植后环磷酰胺(PTCy)单独或与托珠单抗(TOC)联合使用可减轻GVHD。本研究建立了一个临床前GVL人源化小鼠模型,并探讨了PTCy单独或与TOC联合使用是否会影响GVL免疫。 方法 在第 0 天向 NOD-scid-IL2Rγnull 小鼠注射 2 × 107 人外周血单核细胞(hPBMCs),在第 14 天注射 1 × 106 THP-1 急性髓性白血病细胞。在随后的实验中,还在第 3 天和第 4 天向小鼠注射 PTCy(33 毫克/千克)或 Dulbecco 磷酸盐缓冲盐水(PBS),单独或与 TOC 或对照抗体(25 毫克/千克)联合注射,每周两次,共注射 28 天。临床症状监测至第 42 天。 结果 使用三种不同供体的 hPBMC 和 THP-1 细胞的小鼠显示出相似的存活率、临床评分和体重减轻情况。使用两种供体的 hPBMC 重组的小鼠中 hCD33+ 白血病细胞极少,但使用第三种供体的 hPBMC 重组的小鼠中却有,这表明供体特异性 GVL 反应。单用 PTCy 和 PTCy + TOC 处理的 hPBMCs 小鼠显示肝脏 hCD33+ 白血病细胞极少,表明 GVL 免疫持续存在。此外,PTCy + TOC 的组合还减少了肺部和肝脏的组织学损伤。 结论 总的来说,这项研究表明,PTCy 单独或与 TOC 联合使用可在不损害 GVL 免疫力的情况下减轻 GVHD。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Graft-versus-leukaemia immunity is retained following treatment with post-transplant cyclophosphamide alone or combined with tocilizumab in humanised mice

Objectives

Donor haematopoietic stem cell transplantation treats leukaemia by inducing graft-versus-leukaemia (GVL) immunity. However, this benefit is often mitigated by graft-versus-host disease (GVHD), which is reduced by post-transplant cyclophosphamide (PTCy) alone or combined with tocilizumab (TOC) in humanised mice. This study established a preclinical humanised mouse model of GVL and investigated whether PTCy alone or combined with TOC impacts GVL immunity.

Methods

NOD-scid-IL2Rγnull mice were injected with 2 × 107 human peripheral blood mononuclear cells (hPBMCs) on day 0 and with 1 × 106 THP-1 acute myeloid leukaemia cells on day 14. In subsequent experiments, mice were also injected with PTCy (33 mg kg−1) or Dulbecco's phosphate buffered saline (PBS) on days 3 and 4, alone or combined with TOC or control antibody (25 mg kg−1) twice weekly for 28 days. Clinical signs of disease were monitored until day 42.

Results

Mice with hPBMCs from three different donors and THP-1 cells showed similar survival, clinical score and weight loss. hCD33+ leukaemia cells were minimal in mice reconstituted with hPBMCs from two donors but present in mice with hPBMCs from a third donor, suggesting donor-specific GVL responses. hPBMC-injected mice treated with PTCy alone or combined with TOC (PTCy + TOC) demonstrated prolonged survival compared to control mice. PTCy alone and PTCy + TOC-treated mice with hPBMCs showed minimal hepatic hCD33+ leukaemia cells, indicating sustained GVL immunity. Further, the combination of PTCy + TOC reduced histological damage in the lung and liver.

Conclusion

Collectively, this research demonstrates that PTCy alone or combined with TOC impairs GVHD without compromising GVL immunity.

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来源期刊
Clinical & Translational Immunology
Clinical & Translational Immunology Medicine-Immunology and Allergy
CiteScore
12.00
自引率
1.70%
发文量
77
审稿时长
13 weeks
期刊介绍: Clinical & Translational Immunology is an open access, fully peer-reviewed journal devoted to publishing cutting-edge advances in biomedical research for scientists and physicians. The Journal covers fields including cancer biology, cardiovascular research, gene therapy, immunology, vaccine development and disease pathogenesis and therapy at the earliest phases of investigation.
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